Introduction

Current breakpoints in Europe

Seven
different sets of antimicrobial MIC breakpoints are used in Europe. There are
6 active European National Breakpoint Committees: BSAC (UK), CA-SFM (France),
CRG (The Netherlands), DIN (Germany), NWGA (Norway) and SRGA (Sweden) and,
since many of the other countries, in the absence of a national system,
subscribe to breakpoints published by the CLSI (formerly NCCLS),
USA, the divergence in interpretation is
prominent. So far there has been no active co-ordination between the European
National Committees or between Europe
and the USA. To achieve harmonization of antimicrobial breakpoints,
the six National Committees have now organised themselves in EUCAST (European
Committee on Antimicrobial Susceptibility Testing), convened and financed by
ESCMID (European Society for Clinical Microbiology and Infectious Diseases).

EUCAST

EUCAST is a standing committee of ESCMID and consists of a body of experts
appointed by national societies of clinical microbiology and/or infectious
diseases and national breakpoint committees. EUCAST will act with the support
of national breakpoint committees to harmonize breakpoints for existing
antimicrobials and set breakpoints for new antimicrobials. In this
professional consensus process EUCAST will liaise with other professional
groups and organisations.

The
EUCAST General Committee consists of a representative from each European
country and
from ISC and FESCI. All pharmaceutical companies and manufacturers of
susceptibility testing devices can be part of the EUCAST consultation process
by participation in established email consultation groups.

The
EUCAST Steering Committee is the
more active part of EUCAST. Apart from the
Chairman, Scientific Secretary, Clinical Data Co-ordinator and two country representatives from the EUCAST
General Committee (all appointed by the ESCMID board), each of the 6 National Breakpoint Committees
are represented on the steering committee. The national committees consist of 10 - 20
experts in their respective fields. This means that the consultation process
beween EUCAST and the national breakpoint committees is of major importance,
not only to seek the joint approval of steering committee decisions but to
seek scientific answers to difficult questions. Following the internal
consultation process between the steering committee and the national breakpoint
committees, tentative
decisions made by the steering committee are submitted to the EUCAST General
Committee for comments and suggestions.
The final decision rests with the EUCAST Steering committee. The described decision
process is valid for all decisions taken by EUCAST, including decisions on
breakpoints.

For further
information on the structure of EUCAST, see the EUCAST website http://www.eucast.org.

National determination of breakpoints

Each
National Breakpoint Committee consists of 10 – 20 experts within the
fields of clinical microbiology, infectious diseases and pharmacology. Some
have additional experts within the fields of community medicine, pediatrics
and otorhinolaryngology.
Each Committee hasan academic process for setting national
breakpoints for new drugs and for the revision of breakpoints for existing
drugs. These processes vary. Some emphasize the pharmacokinetic/pharmacodynamic
aspects while others emphasize microbiological factors. Several committees have representation from
the pharmaceutical and antimicrobial susceptibility testing industry while
others do not.

EUCAST will
make use of existing national processes for determining clinical breakpoints
for new antimicrobials and for revising and harmonising breakpoints for
existing drugs. The work has started with the revision of breakpoints for fluoroquinolones, aminoglycosides, glycopeptides and linezolid.EUCAST will try a co-ordinated process for setting breakpoints
for new antimicrobials (see below).

In addition
to clinical breakpoints, EUCAST will define epidemiological cut-off values,
which are related to the distribution of MICs of wild type susceptible
populations and are of value in detecting the development of microbiological
resistance to antimicrobial agents.

Breakpoints for new antimicrobials

The procedure through which EMEA, EUCAST and
Pharmaceutical industry interact in the approval process for new drugs is
defined in an SOP (SOP /H/3043, 14 February 2005).

The national committees
(BSAC, CA-SFM, CRG, DIN, NWGA, SRGA)have agreed to notify each other when one or several are
approached to set breakpoints for a new antimicrobial drug outside of the EMEA
procedure.

The
advantages of the agreed procedure are that it results in common European
clinical breakpoints for new antimicrobials, the procedure has a time limit,
the expertise within the system is fully utilized and it is cost effective
for the drug companies (one file, one presentation of the drug, a common
European breakpoint).

Each
national breakpoint committee will submit (using a form designed for this
purpose):

A preliminary breakpoint for the agent in question. Unless the agent belongs to
a class of dugs which has been through the EUCAST harmonization process, the
national clinical breakpoints of related drugs should be presented
simultaneously.

The nationally
recommended dosages of the agent being assessed and the available
formulations.

Thenational recommended indications for the new drug.

MIC
distributions of relevant species.

Data collation

The EUCAST
secretariat will:

Collate
all information in one file and other pertinent information. This file is distributed to the National
Committees for ratification.

Enter the
MIC-distributions into the “EUCAST antimicrobial wild-type software”,
thereby making all MIC distributions available to all National Committees on
the internet.

Modelling processes,
such as Monte Carlo simulation, may be used to assist the
process of breakpoint setting.

Clinical data
relating outcome to MIC-values

Breakpoints suggested by the national
breakpoint committees are compared and discussed.

Consensus
breakpoints are
sought.

Resulting breakpoints are tested against each of the major target
species MIC-distributions. This is to make sure that the suggested EUCAST
breakpoints do not divide the wild-type distributions of major target
species. This would obviate a reproducible S, I & R- categorisation in the
laboratory. The ensuing breakpoints may therefore differ between species.

The committee may refrain from setting breakpoints if the
species is considered a poor target for the drug (marked by ─ in breakpoint tables)
or there is insufficient evidence
that the species is a good target for the drug (marked by IE in breakpoint
tables)

Consultation on preliminary breakpoints

Preliminary EUCAST breakpoints on new drugs are presented to national breakpoint
committees for comments. Significant points arising will be discussed in the
Steering Committee and any adjustments agreed.

The
tentative EUCAST breakpoints are then submitted for comments to the EUCAST
General Committee members, the EMEA and the drug companies and again to
national breakpoint committees.

Presentation of breakpoints

EUCAST
breakpoints are presented as "tentative
breakpoints for comments"
in tables freely accessible on the EUCAST website.
Major groups of organisms each have a breakpoint column.
Current groups are Enterobacteriaceae, Pseudomonas, Acinetobacter,
staphylococci, Streptococcus pneumoniae, streptococci, enterococci,
Haemophilus, Moraxella, Neisseria gonorrhoeae, Neisseria
meningitidisand anaerobes (Bacteroides spp/clostridia).
In addition, a column of non-species related
breakpoints determined mainly on the basis of PK/PD data and
independent of MIC distributions of specific species are presented. These are for use only
for species that have not been given a species-specific breakpoint and not for
those species where susceptibility testing is not recommended.
See exampleson the EUCAST website.

The EUCAST General
Committee and the manufacturer´s network are
notified of the "tentative breakpoints for comments".

Finalisation of EUCAST breakpoints

Comments
received in writing during the consultation period are made available
(published on the steering committee website) to the national committees and
to the steering committee members. Comments are discussed at the following
EUCAST Steering Committee meeting and a consensus decision reached. In the
case of a dissenting National Committee, they will submit their reasoning in
writing, and this will be published with the breakpoint agreed on by the rest
of the Steering Committee.

Publication of breakpoints

Breakpoints will be published on
the EUCAST website, on the National Committee websites and in publications. A
document will be prepared for publication in CMI.

Harmonizing
breakpoints for existing antimicrobials

Each of the
existing groups of antimicrobials will be addressed in turn. The work
has started
with the fluoroquinolones, aminoglycosides, glycopeptides and linezolid and is
now continuing with carbapenems and cephalosporins. For existing drugs the process will be a revision exercise,
involving an element of compromise to achieve harmonization of breakpoints.
Decisions in the Steering Committee are taken by consensus agreement. The process involves consultation with the EUCAST General Committee,
pharmaceutical industry, antimicrobial susceptibility testing industry and
EMEA.

Data
collection

Each
national breakpoint committee will submit (using a form designed for this
purpose):

The
current breakpoint(s) for the relevant agent(s). Those that have been
recently re-evaluated will be indicated. It is important that each National
Committee representative informs their National Committee of the forthcoming
re-evaluation of the respective breakpoints. Ideally the National Committee
should give the Steering Committee representative an “acceptable” MIC range
for breakpoints to allow for compromise if necessary.

The
national maximum and minimum dosages of the agents being assessed and the
available formulations.

The
nationally accepted clinical indications and the microbial targets for each
of the agents being assessed.

MIC
distributions of relevant species, preferably those that were used in the
national process of breakpoint setting.

Data collation

The EUCAST
secretariat will

Collate
all information in one file (see enclosed example of the fluoroquinolones)
and other pertinent
information. This file is distributed to the National Committees for
ratification.

Enter the
MIC-distributions into the “EUCAST antimicrobial wild-type software”,
thereby making all MIC distributions available to all National Committees on
the internet.

Modelling processes,
such as Monte Carlo simulation, may be used to assist the
process of breakpoint setting.

Clinical data
relating outcome to MIC-values

Existing national
breakpoints are compared.

Consensus
breakpoints are
sought.

Resulting breakpoints are tested against each of the major target
species MIC-distributions. This is to make sure that the suggested EUCAST
breakpoints do not divide the wild-type distributions of major target
species. This would obviate a reproducible S, I & R- categorisation in the
laboratory. The ensuing breakpoints may therefore differ between species.

The committee may refrain from setting breakpoints if the
species is considered a poor target for the drug (marked by ─ in breakpoint tables) or there is insufficient evidence
that the species is a good target for the drug (marked by IE in breakpoint
tables)

Consultation on preliminary breakpoints

Tentative EUCAST breakpoints are presented to national breakpoint
committees for comments. Significant points arising will be discussed in the
Steering Committee and any adjustments agreed.

The
tentative EUCAST breakpoints are then submitted for comments to the EUCAST
General Committee members, the EMEA and the drug companies and again to
national breakpoint committees for comments.

Presentation of breakpoints

EUCAST
breakpoints are presented as "tentative
breakpoints for comments"
in tables freely accessible on the EUCAST website.
Major groups of organisms each have a breakpoint column.
Current groups are Enterobacteriaceae, Pseudomonas, Acinetobacter,
staphylococci, Streptococcus pneumoniae, streptococci, enterococci,
Haemophilus, Moraxella, Neisseria gonorrhoeae, Neisseria
meningitidisand anaerobes (Bacteroides spp/clostridia).
In addition, a column of non-species related
breakpoints determined mainly on the basis of PK/PD data and
independent of MIC distributions of specific species are presented. These are for use only
for species that have not been given a species-specific breakpoint and not for
those species where susceptibility testing is not recommended.
See exampleson the EUCAST website.

The EUCAST General
Committee and the manufacturer´s network are
notified of the "tentative breakpoints for comments".

Finalisation of EUCAST breakpoints

Comments received in writing during the
two-month
consultation period are made available
to the national committees and to the steering committee members. Comments are
discussed at the following EUCAST Steering Committee and
a
consensus decision reached. If
one of the
National Committees cannot agree with
the consensus decision,
their reasoning
will be submitted
in writing, and this will be published with the breakpoint agreed by the rest
of the Steering Committee.

Publication of breakpoints

Breakpoints will be published on
the EUCAST website, on the National Breakpoint Committee websites and in publications. A
document will be prepared for publication in CMI.